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MBC in Press, published online ahead of print June 23, 2004
Mol. Biol. Cell 10.1091/mbc.E04-01-0024

A more recent version of this article appeared on September 1, 2004
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Submitted on January 12, 2004
Revised on May 13, 2004
Accepted on June 8, 2004

CFTR Degradation Depends on the Lectins Htm1p/EDEM and the Cdc48 Protein Complex in Yeast

Andreas Gnann*, John R. Riordan{dagger}, and Dieter H. Wolf*{ddagger}

*Institut für Biochemie, Universität Stuttgart, 70569 Stuttgart, Germany; and {dagger}S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, AZ 85259

Monitoring Editor: Peter Walter

Cystic fibrosis is the most widespread hereditary disease among the white population caused by different mutations of the apical membrane ABC transporter cystic fibrosis transmembrane conductance regulator (CFTR). Its most common mutation, {Delta}F508, leads to nearly complete degradation via ERAD. Elucidation of the quality control and degradation mechanisms might give rise to new therapeutic approaches to cure this disease. In the yeast Saccharomyces cerevisiae a variety of components of the protein quality control and degradation system have been identified. Nearly all of these components share homology with mammalian counterparts. We therefore used yeast mutants defective in the ERAD system to identify new components which are involved in human CFTR quality control and degradation. We show the role of the lectin Htm1p in the degradation process of CFTR. Complementation of the HTM1 deficiency in yeast cells by the mammalian orthologue EDEM underlines the necessity of this lectin for CFTR degradation and highlights the similarity of quality control and ERAD in yeast and mammals. Furthermore, degradation of CFTR requires the ubiquitin protein ligases Der3p/Hrd1p and Doa10p as well as the cytosolic trimeric Cdc48p-Ufd1p-Npl4p complex. These proteins were also found to be necessary for ERAD of a mutated yeast "relative" of CFTR, Pdr5*p.

{ddagger}Corresponding author. E-mail: dieter.wolf{at}po.uni-stuttgart.de




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